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Second Edition Electrophysiological Foundations Andrew L. Wit of Cardiac Arrhythmias Penelope A. Boyden A Bridge Between Basic Mechanisms and Electrophysiological Foundations of Cardiac Arrhythmias Clinical Electrophysiology Mark E. Josephson Second Edition Hein J. Wellens

Now in an abridged second edition, Electrophysiological Foundations of Cardiac

Arrhythmias focuses on teaching the fundamental concepts of cardiac cellular Wit • Boyden Josephson Wellens electrophysiology with an emphasis on the relationship of basic mechanisms to clinical cardiac arrhythmias. Understanding this relationship and the electrophysiological mechanisms underlying arrhythmogenesis will be invaluable Electrophysiological to physicians entering the fields of cardiology and clinical electrophysiology, as well as those scientists and clinicians already working in these areas.

These essential concepts of electrophysiology include discussion on action potentials, ion channels and currents, and mechanisms of arrhythmias, and Foundations of provide the working knowledge that will enable the reader to approach a board exam confidently. Additionally, the authors build a base of understanding that will prepare the reader for more advanced texts, such as Josephson’s Clinical Cardiac Electrophysiology: Techniques and Interpretations. Cardiac Arrhythmias

About the Authors The authors, Andrew L. Wit, PhD, Penelope A. Boyden, PhD, Mark E. Josephson, A Bridge Between MD, and Hein J. Wellens, MD, PhD, have spent four lifetimes investigating and defining electrophysiological mechanisms of cardiac arrhythmias. But equally important, they have devoted their careers to teaching this subject to students of all levels, from medical Basic Mechanisms and students to more advanced cardiology and clinical electrophysiology fellows. Clinical Electrophysiology

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Andrew L. Wit, PhD Penelope A. Boyden, PhD Mark E. Josephson, MD Hein J. Wellens, MD, PhD Second Edition

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Printed in Canada Table of Contents

About the Authors ix Preface: Why Is Basic Cardiac Electrophysiology Important? xi Introduction: How This Book Is Organized xiii Abbreviations and Ionic Currents Involved in Arrhythmogenesis xv

CHAPTER 1: Basic Principles of Normal Automaticity 1 General Principles of Normal Automaticity 2

CHAPTER 2: Sinus Node Normal Automaticity and Automatic Arrhythmias 15 Basic Electrophysiological Mechanisms 15 Examples of Arrhythmias Caused by Alterations in Sinus Node Automaticity 37

CHAPTER 3: Atrial, A-V Junctional, and Ventricular Normal Automaticity and Automatic Arrhythmias 45 SECTION 3A: Atrial Normal Automaticity and Automatic Arrhythmias 45 Basic Electrophysiological Mechanisms 45 Examples of Arrhythmias Caused by Atrial Automaticity 49 SECTION 3B: Atrioventricular (A-V) Junctional Normal Automaticity and Automatic Arrhythmias 59 Basic Electrophysiological Mechanisms 59 Examples of Arrhythmias Caused by Alterations in A-V Junctional Automaticity 66 SECTION 3C: Ventricular Normal Automaticity and Automatic Arrhythmias 79 Basic Electrophysiological Mechanisms 79 Examples of Arrhythmias Caused by Alterations in Ventricular Automaticity 82

CHAPTER 4: Abnormal Automaticity: Basic Principles and Arrhythmias 97 Basic Electrophysiological Mechanisms of Abnormal Automaticity 97 Examples of Arrhythmias Caused by Abnormal Automaticity 107

CHAPTER 5: Basic Principles of Delayed Afterdepolarizations (DADs) and Triggered Action Potentials 113

CHAPTER 6: Delayed Afterdepolarizations: Triggered Arrhythmias 133 SECTION 6A: Atrial Delayed Afterdepolarizations and Triggered Arrhythmias 133 Basic Electrophysiological Mechanisms 133 Examples of Arrhythmias Caused by DAD-Triggered Activity in the Atria 134 SECTION 6B: Atrioventricular (A-V) Junctional Delayed Afterdepolarizations and Triggered Arrhythmias 142 Basic Electrophysiologic Mechanisms 142 Examples of Arrhythmias Caused by DAD-Triggered Activity 142 SECTION 6C: Ventricular Delayed Afterdepolarizations and Triggered Arrhythmias 151 Basic Electrophysiological Mechanisms 151 Examples of Arrhythmias Caused by DAD-Triggered Activity in the Ventricle 151

vii viii ¢ Electrophysiological Foundations of Cardiac Arrhythmias: A Bridge Between Basic Mechanisms and Clinical Electrophysiology, Second Edition

CHAPTER 7: Basic Principles of Early Afterdepolarizations and Triggered Action Potentials 167

CHAPTER 8: Early Afterdepolarizations: Triggered Arrhythmias 185 Congenital Long QT (LQT) Syndromes 185 Long QT Caused by Structural Heart Disease and/or Ischemia 190 Acquired Long QT Syndrome 191

CHAPTER 9: Basic Principles of Reentry: Altered Conduction and Reentrant Excitation 197 Overview and General Principles 197

CHAPTER 10: Atrial Reentrant Arrhythmias 243 SECTION 10A: Atrial Tachycardias Caused by Reentry in Macroreentrant Circuits 243 SECTION 10B: Atrial Tachycardia Caused by Reentry in Small (Micro) Reentrant Circuits; Focal Reentrant Tachycardia 261 SECTION 10C: Atrial Fibrillation 265

CHAPTER 11: Atrioventricular (A-V) Junctional Reentrant Arrhythmias 277 Reentrant Excitation in the Normal A-V Junction 277 Reentrant Excitation Utilizing an Accessory A-V Conducting Pathway 289

CHAPTER 12: Ventricular Reentrant Arrhythmias 307 Reentry Associated With Nonischemic Cardiomyopathy 324 Reentry in the Ventricular Conducting System 330 Other Reentrant Arrhythmias 338

Index 343 PREFACE Why Is Basic Cardiac Electrophysiology Important?

pproximately 55 years ago, the introduction of pro- cardiac electrophysiology must have a solid basic knowl- grammed electrical stimulation of the heart edge foundation of basic electrophysiology. Atogether with the recording of intracardiac electro- This book is designed to lead the reader through the grams, including that of the bundle of His, opened the door pathway from basic cardiac electrophysiology over the for better understanding of the underlying mechanisms of bridge to clinical cardiac electrophysiology. Basic cellular different types of cardiac arrhythmias. This initial diagnos- electrophysiology of the three main categories of arrhyth- tic phase led to new therapeutic possibilities, such as mogenesis (automaticity, triggered activity, and arrhythmia surgery, better selection of antiarrhythmic reentry—see the Introduction and Table i-1) is described in drugs, antitachycardia pacing, and catheter ablation. In sufficient detail to understand how alterations in cellular those 55 years, the number of cardiologists involved in car- electrophysiology cause an arrhythmia. Then, these cellu- diac arrhythmia management and the complexity of lar electrophysiological mechanisms are related to the ECG diagnosis and treatment options increased remarkably. appearance of that arrhythmia and how the arrhythmia Of great importance has been a parallel increase in responds to interventions such as programmed electrical knowledge of the basic electrophysiology of the heart that stimulation and selected pharmacological agents that are has been essential for understanding the mechanisms of mechanism-specific. Therapy for arrhythmias is not part arrhythmogenesis and their clinical expression. A major of this curriculum. factor was the introduction of the microelectrode tech- In writing this book, it has not been our intent to pro- nique for recording transmembrane action potentials vide a complete review or description of either the basic or from heart cells. This has led the authors of this book to the clinical electrophysiology of the heart. These fields are the firm belief that practitioners of clinical cardiac elec- now so extensive that a complete review of both would be trophysiology should have a solid foundation in the basic impossible undertakings for the authors and would electrophysiology responsible for the rhythm abnormali- require a number of contributors who are expert in all ties that they are treating. This reasoning is two-fold. aspects of both basic and clinical cardiac electrophysiol- First, understanding the electrophysiologic mechanism ogy. Rather, it is our purpose to provide the basic of an arrhythmia can help in selecting the appropriate foundations of both cellular electrophysiology and the treatment. Initially, the mechanism may not always be evi- electrophysiology of selected arrhythmias, so that readers dent, but requires some probing to discover it. Appropriate will be able to advance their education with additional reasoning and interpretations of test results to successfully texts written by experts. These texts typically assume the identify the mechanism is based on knowledge of the elec- fundamental knowledge of basic and clinical electrophysi- trophysiological properties of the different mechanisms. ology found in this book. Second, the development of modern clinical cardiac This is the second edition of the book originally pub- electrophysiology has been built on a foundation of the lished in 2017. We have tried to make it more user-friendly basic science of cardiac electrophysiology, without which by eliminating details that may not have been necessary the discipline would have stagnated. Discoveries that have for the understanding of basic concepts, shortening the moved the field forward and enabled it to accomplish pre- book by about a third. viously unimaginable goals have been based on the Andrew L. Wit, PhD interactions of laboratory and clinical research on basic Penelope A. Boyden, PhD mechanisms. For expert clinical practice and to make new Mark E. Josephson, MD discoveries in the field, current practitioners of clinical Hein J. Wellens, MD, PhD xi INTRODUCTION How This Book Is Organized

lthough there are many kinds of clinical arrhyth- Table i-1 subdivides the causes for impulse initiation mias with many different pathological causes, in into two categories: (A) automaticity and (B) triggered Athe final analysis, they all are the result of critical activity. Each has its own unique cellular mechanism alterations in cardiac cellular electrophysiology. Since cel- resulting in the membrane depolarization that initiates lular electrophysiology is so important, it is the foundation impulses. for the description of mechanisms causing arrhythmias in this book. It is presented in the context of an arrhythmia Automaticity mechanism and examples of the clinical arrhythmias that Automaticity is the result of spontaneous (diastolic) depo- this mechanism causes. larization (SDD). Chapters 1–4 describe the cellular The different cellular mechanisms that form the orga- mechanisms of automaticity and provide examples of the nization of the book are presented in Table i-1. clinical arrhythmias that it causes. Automaticity is divided Table i-1 Electrophysiological Mechanisms of Cardiac Arrhythmias into two kinds, normal (Chapters 1–3) and abnormal (Chapter 4). Normal automaticity is found in the primary I. Abnormal Impulse Initiation pacemaker of the heart—the sinus node (Chapter 2)—as A. Automaticity well as in subsidiary or latent pacemakers found in certain • normal automaticity regions of the atria, A-V junction, and ventricular special- • abnormal automaticity ized conducting system (Chapter 3). Impulse initiation is B. Triggered Activity a normal property of these latent pacemakers. • delayed afterdepolarizations On the other hand, abnormal automaticity (Chapter 4) • early afterdepolarizations occurs in cardiac cells when major (abnormal) changes II. Altered (Abnormal) Impulse Conduction occur in their transmembrane potentials due to pathology. Working atrial and ventricular myocardial cells do A. Conduction block leading to ectopic pacemaker “escape” not normally have spontaneous diastolic depolarization B. Unidirectional block and reentry and do not normally initiate spontaneous impulses. • anatomical reentry However, when their resting potentials are reduced suffi- • functional reentry ciently by disease, spontaneous diastolic depolarization (Modified from Hoffman, BF, Rosen MR. Cellular mechanisms of cardiac may occur and cause repetitive impulse initiation, a phe- arrhythmias. Circ Res. 1981;49:1–15.) nomenon called depolarization-induced abnormal automaticity. Atrial and ventricular tachycardias occur- ABNORMAL IMPULSE INITIATION ring in a number of different diseases can be caused by abnormal automaticity. This topic constitutes Chapters 1–8 of this book. The term “impulse initiation” is used to describe an electrical signal Triggered Activity (impulse) that arises in a single cell or group of closely Triggered activity (Table i-1 B), is a form of impulse initia- coupled cells through depolarization (decrease in negativ- tion caused by afterdepolarizations. Afterdepolarizations ity) of the cell membrane potential to a threshold that are abnormal oscillations in membrane potential that initiates an action potential. Once initiated, the action occur after the rapid depolarization (Phase 0) of an action potential(s) form an electrical impulse that spreads to potential. Chapters 5–8 describe the electrophysiological other regions of the heart. mechanisms for afterdepolarizations and provides

xiii xiv ¢ Electrophysiological Foundations of Cardiac Arrhythmias: A Bridge Between Basic Mechanisms and Clinical Electrophysiology, Second Edition

examples of the clinical arrhythmias that they cause. responses to electrical stimulation and some pharmaco- There are two types of afterdepolarizations that cause logical agents. triggered activity. One type is delayed until repolarization Chapters 10–12 describe the process of reentry in dif- is complete or nearly complete (delayed afterdepolariza- ferent regions of the heart (atria, A-V junction, ventricles). tions [DADs]) (Chapters 5 and 6). The other type is early, Each chapter also provides example arrhythmias that are occurring before repolarization is complete (early after caused by this mechanism. depolarizations [EADs]) (Chapters 7 and 8). THE BRIDGE BETWEEN BASIC MECHANISMS ALTERED (ABNORMAL) IMPULSE CONDUCTION AND CLINICAL ELECTROPHYSIOLOGY Altered (abnormal) impulse conduction (heading II in The purpose of this book is to explain how basic cardiac Table i-1) includes both arrhythmias due to conduction electrophysiology can elucidate mechanisms causing car- block leading to ectopic pacemaker escape and arrhyth- diac arrhythmias, that is, to provide a bridge between mias due to unidirectional block and reentry. basic mechanisms and clinical electrophysiology. Concepts from basic electrophysiology are interwoven with the Conduction Block Leading to arrhythmia mechanisms and examples of clinical arrhyth- Ectopic Pacemaker “Escape” mias in order to show the close interrelationships between basic and clinical electrophysiology. With the appropriate Conduction block leading to ectopic pacemaker “escape” background from medical school physiology, we hope (subheading II, A) is described in Chapters 1–4 as a these basic concepts are understandable as encountered mechanism for occurrence of some arrhythmias caused while progressing through the book. by normal and abnormal automaticity. This same bridge is also a pathway from clinical arrhythmias to basic mechanisms. It is our belief that as Unidirectional Block and Reentry the student becomes more familiar with the mechanisms Unidirectional block and reentry are the subjects of of arrhythmogenesis, the information obtained from Chapters 9–12. Chapter 9 describes the basic cellular clinical electrophysiology will become easier to assimilate electrophysiology of impulse conduction in the heart and and to utilize for improved diagnosis and treatment of how this process is altered by disease to slow it or to cause real-world arrhythmias. it to fail (conduction block). These basic cellular concepts are then applied to the different mechanisms that cause SOURCES reentrant excitation, a process whereby the propagating impulse can circulate and return to re-excite regions that Josephson ME. Josephson’s Clinical Cardiac Electrophysiology: it has already excited without the requirement for new Techniques and Interpretations (5th ed.). Philadelphia, PA: impulse initiation. Reentrant circuits are described that Wolters Kluwer; 2016. Wellens HJJ, Conover M. The ECG in Emergency Decision Making. St. are dependent on anatomical structures as well as func- Louis, MO: Saunders Elsevier; 2006. tional properties of cardiac muscle and the characteristic CHAPTER

Basic Principles of Normal Automaticity 1

utomaticity is the term used to indicate the mech- mechanism by which certain myocardial cells can generate anism for the initiation of an electrical signal in a impulses spontaneously by normal automaticity. Asingle cell or group of closely interacting (coupled) The cause of normal automaticity in the sinus node and cells. This signal, in the form of an action potential, arises latent pacemakers is a spontaneous decline (becoming less from spontaneous depolarization of the membrane poten- negative) in the membrane potential during diastole or tial. The action potential is the electrical signal or impulse phase 4. This decline in membrane potential is referred to that excites the heart, and the cell(s) that generate this as either the “pacemaker potential,” “phase 4 depolariza- signal are called “pacemakers.” tion,” or “spontaneous diastolic depolarization” (SDD). “Normal automaticity” is found in the primary pace- Figure 1-1 illustrates an action potential with a pacemaker maker of the heart, the sinus node, as well as in certain potential in a myocardial cell with the property of normal subsidiary or latent pacemakers that can become the pace- automaticity and compares the automatic cell with a cell maker under special conditions (hence the term, latent). without normal automaticity (nonautomatic cell). Impulse initiation is an intrinsic property of these latent Panel A shows a nonautomatic cell with a steady level pacemakers, as it is in the sinus node. (“Abnormal automa- of resting (diastolic) potential during phase 4 (the resting ticity,” described in Chapter 4, is related to pathological potential [RP]) between action potentials (purple arrow). changes in a region of the heart, often where the cells do This type of cell must be excited from an external source not have intrinsic pacemaker properties, although there (green arrow), either another connected cell or an are exceptions.) The recording of the transmembrane rest- applied electrical stimulus, to initiate an action poten- ing potential (often referred to here as simply the membrane tial. The action potential is comprised of phase 0 (rapid potential) and action potentials as well as the membrane depolarization phase or “upstroke”) and phases 1, 2, and currents of individual myocardial cells has provided much 3 (repolarization phases). of the information necessary for understanding the

Figure 1-1 Diagrams of transmembrane action potentials characteristic of a nonautomatic cell (Panel A) and a normal automatic cell (Panel B). In each panel, the horizontal black line indicates “0” potential and the horizontal dashed line is the threshold potential (TP).

1 Electrophysiological Foundations of Cardiac Arrhythmias: A Bridge Between Basic Mechanisms and Clinical Electrophysiology, Second Edition. © 2020 Andrew L. Wit, Penelope A. Boyden, Mark E. Josephson, Hein J. Wellens. Cardiotext Publishing, ISBN: 978-1-942909-42-2. 2 ¢ Chapter 1: Basic Principles of Normal Automaticity

Panel B shows a cell with normal automaticity. ¢ The level of the “maximum diastolic potential” Spontaneous diastolic depolarization (the pacemaker (MDP), which is the maximum negativity attained potential) is that part of the membrane potential labeled after repolarization of the action potential. This “SDD” (black arrow) coinciding with phase 4 of the mem- term is used instead of resting potential (RP) since brane potential. In Panel B, the membrane potential moves the membrane potential in a pacemaker cell does not spontaneously in a positive direction from the maximum have a period of rest as it does in a nonpacemaker potential during diastole (maximum diastolic potential cell (Figure 1-1, Panel B). [MDP]) with a negative value of –70 mV until it reaches the ¢ The level of the “threshold potential” (TP) for threshold potential (TP), which is less negative at –60 mV. initiation of phase 0 of the action potential. The At this point, the inward depolarizing current (phase 0, red threshold potential is the membrane potential at arrow) is activated, and this in turn causes the cell to gen- which the inward current causing phase 0 becomes erate an action potential. Phase 0 is responsible for regenerative to cause a conducted action potential. conduction of the action potential from the pacemaker cell to surrounding cells. Depolarization of membrane poten- ¢ The slope of “spontaneous diastolic depolarization” tial during SDD represents the summation of a number of (SDD), which is the rate of change of phase 4, also inward and outward transmembrane currents with depo- referred to as the pacemaker potential. This slope is larization resulting because inward current dominates. dependent on the speed of activation and the In later chapters, we describe the specific ion channels magnitude of net inward current. Sometimes there and membrane currents that are involved in the genesis of may be two different slopes if the rate of change is the pacemaker depolarization, but these details are not not constant. necessary at this point for understanding the role of auto- ¢ The “action potential duration” (APD) is the time maticity in causing arrhythmias. from depolarization phase 0 to complete repolarization at the end of phase 3. General Principles of Normal These features of the transmembrane potential are Automaticity under the control of the ion channels, pumps, and exchangers involved in the genesis of the pacemaker potential and 1. Control of rate of automatic impulse initiation action potential, which will be described in detail later in this chapter and in Chapters 2 and 3. A change in any one 2. Relationship between sinus node and latent of the above parameters caused by changes in the mem- pacemakers brane currents will alter the time required for SDD to 3. Electrophysiological causes of ectopic automatic move the membrane potential from its MDP to the TP, and arrhythmias thereby alter the rate of impulse initiation. Understanding 4. General ECG characteristics of automatic the interplay of these factors is necessary for understand- arrhythmias ing how automatic arrhythmias occur. 5. Effects of electrical stimulation and pharmacological agents on normal automaticity

CONTROL OF RATE OF AUTOMATIC IMPULSE INITIATION The rate of automatic impulse initiation is determined by two major factors: the characteristics of the transmembrane potential and electrical coupling between pacemaker and nonpacemaker cells.

Transmembrane Potential The intrinsic rate at which pacemaker cells initiate impulses is determined by the amount of time it takes for the membrane potential to move from its maximal negativity Figure 1-2 Factors that control intrinsic rate. Panel A shows effects (maximum diastolic potential, MDP) after repolarization of changes in slope of spontaneous diastolic depolarization (SDD). to the threshold potential to generate an action potential or Panel B shows effects of changes in maximum diastolic potential (MDP). impulse. Time to threshold potential is in turn dependent Panel C shows effects of changes in threshold potential (TP). Panel D on the interplay of several factors (Figure 1-2), including: shows effects of changes in action potential duration (APD). Control of Rate of Automatic Impulse Initiation ¢ 3

Figure 1-2 illustrates how these parameters control the potential) to the less negative TP (blue dashed line, labeled spontaneous rate. Panel A shows how changes in the slope 1), then the SDD must proceed for a longer time before an of SDD can change the rate of automatic impulse initia- impulse is finally initiated (rapid upstroke, solid blue tion. The red trace shows action potentials with the initial trace). Thus the heart rate is slower. Conversely, an intrinsic or automatic rate of the pacemaker cell, that is increase in TP (from red to more negative green dashed determined by the time required for SDD caused by the line, labeled 2) accelerates the heart rate because SDD pacemaker current(s), to move the membrane potential must proceed for a shorter time before an impulse is initi- from the MDP to TP. The blue trace (labeled 1) shows the ated, shown by the earlier green action potential. effect of a decrease in the slope of SDD. This would be Don’t be confused by this terminology corresponding caused by a decrease in net inward pacemaker current, to negative values in which an increase in “potential”— resulting in a longer interval between action potentials and the difference between the measured value and 0—is a decrease in heart rate because of the longer time required actually more negative, while a decrease in potential is for membrane potential to reach the threshold potential. less negative. On the other hand, when the term “thresh- Modest parasympathetic (vagal) activation is one condi- old” is used by itself, an increase in threshold means tion that results in a decreased slope of SDD of sinus node “more difficult to excite” while a decrease in threshold pacemaker cells to slow the heart rate. Some antiarrhyth- means “more excitable.” mic drugs also have this effect on latent pacemakers. The Figure 1-2, Panel D, shows how changes in the APD can green trace (labeled 2) shows the effect of an increase in the alter the rate of impulse initiation. The APD is controlled slope of SDD that increases heart rate. This would be in part by the membrane currents that determine the time caused by an increase in the net inward pacemaker cur- course for repolarization (phases 1, 2, and 3). SDD begins rent, which reduces the time to reach threshold potential after completion of action potential repolarization. If APD and decreases the time between action potentials. lengthens (increases), as illustrated by the change from the Sympathetic activation, which accelerates the heart rate, is red action potential at the left to the blue action potential an example of this condition. (labeled 1) at the left, and the diastolic time remains con- Figure 1-2, Panel B illustrates how a change in the stant, the rate of impulse initiation decreases (compare MDP can change the rate of automatic impulse initiation. onset of the second red action potential with the later sec- If the MDP increases (becomes more negative), going ond blue action potential). A decrease in action potential from the nadir of the solid red trace (initial intrinsic duration shown by the green action potential (labeled 2) at value) to the blue trace (labeled 1), then the SDD (or pace- the left compared with the red action potential, accelerates maker potential) takes longer to reach threshold potential the rate (compare the earlier onset of the second green and the rate of impulse initiation slows. This occurs even action potential with the later onset of the second red if the slope of the SDD is not altered as shown in the fig- action potential) when diastolic time remains constant. ure. An increase in MDP results from a net increase in Changes in APD do not normally apply to the physiolog outward current during diastole which usually is also ical control of rate, but may be instrumental in the rate accompanied by a decrease in slope of SDD. Strong vagal effect of drugs that alter repolarization. activation causes an increase in MDP of sinus pacemaker cells in addition to the decreased slope of SDD, both of Electrical Coupling Between Pacemaker which slow sinus rate. Conversely, a decrease in the MDP (going from red to green trace, labeled 2), decreases the and Nonpacemaker Cells time it takes to go from MDP to TP and increases the rate In addition to the changes discussed in Figure 1-2, electri- of impulse initiation even if the slope of SDD is not altered cal coupling between pacemaker and nonpacemaker cells as shown in the figure. However, a decrease in outward provided by gap junctions, reduces the slope of SDD and current during diastole that decreases MDP, often slows or inhibits pacemaker cell impulse initiation by increases the slope of SDD. A simultaneous increase in electrotonic current flow. The way this effect is exerted is sympathetic activity and decrease in vagal activity can diagrammed in Figure 1-3. produce this change and increase the sinus rate. The lower part of the figure diagrams two adjacent Figure 1-2, Panel C illustrates the effect of changes in cells, P and NP (yellow cylinder). Cell P is a pacemaker cell TP on the rate of impulse initiation. The TP (dashed lines) (action potential is above it) with SDD (black trace) and is the membrane potential required for initiation of the cell NP is a nonpacemaker cell (action potential is above it) upstroke (phase 0) of the action potential. When the TP is with a more negative membrane potential during phase 4 decreased from the initial level indicated by the red (black trace). The broken double black lines between the dashed line (associated with the solid red line action two cells represents the adjacent cell membranes 4 ¢ Chapter 1: Basic Principles of Normal Automaticity

(sarcolemmae) of each cell, which abut to form the interca- retards SDD (red arrow shows shift in slope of SDD from lated disk. In the disks are structures called “gap junctions,” black to red trace) in the pacemaker cell. It also decreases specialized regions of close interaction between the sarco- the membrane potential of the nonpacemaker cell (red lemmae of neighboring myocytes in which clusters of arrow in NP, from black to red trace). channels, formed by proteins called connexins, bridge the The efficacy of this inhibitory effect of electrotonic cur- paired plasma membranes to connect the intracellular rent flow on SDD is dependent on the magnitude of the spaces of cell P and cell NP. Because gap-junctional mem- electrotonic current, which in turn is influenced by the brane is several orders of magnitude more permeable than conductance (ability to pass current) of the gap junctions. nonjunctional plasma membrane, it provides low resis- One determinant of conductance is the isoform of the con- tance pathways for “electrotonic current flow” between nexin protein that forms the gap junction. There are five myocardial cells (represented by the curved black arrows), connexin isoforms that form gap junctions in the human which is important for impulse propagation. (The mecha- heart. The conventional nomenclature for a connexin (Cx) nism for impulse propagation is described in detail in, includes a suffix referring to its molecular weight. Some Chapter 9, Figure 9-4). Electrotonic current flow in the connexin proteins (Cx40 and Cx43) have high conduc- absence of propagation also influences impulse initiation tance, and others (Cx45) have low conductance. Different by automaticity. types of connexins are located in different regions of the heart. In the sinus node region, where pacemaker cells are coupled to nonpacemaker atrial cells with a more negative membrane potential, it is important that the gap junctions between the two cell types have low conductance, or sinus node pacemaker activity might be silenced. However, the conductance must still be sufficient to allow impulse propagation. More details on gap junction function are described in Chapters 2–4, since a decrease in coupling between cells caused by changes in gap junctions can enhance automaticity and cause arrhythmias.

RELATIONSHIP BETWEEN SINUS NODE AND LATENT PACEMAKERS Cells with normal pacemaker properties occur throughout the heart. There is a hierarchy of pacemaker impulse initiation such that the sinus node is normally the primary pacemaker. With the sinus node functioning Figure 1-3 Influence of electrical coupling of pacemaker cell (P) to normally, other pacemaker sites are effectively “silent.” nonpacemaker cell (NP) on spontaneous diastolic depolarization (SDD). Why does impulse initiation in the normal heart reside in the sinus node and not at one of the ectopic sites, since During SDD, the membrane potential in the pacemaker they also have the property of normal automaticity? Two cell (black trace in P) becomes much less negative than the factors are involved: the hierarchy of pacemakers and membrane potential in the adjacent well coupled nonpace- overdrive suppression. maker cell (black trace in NP). As a result of this potential difference, current (positive charges) flows intracellularly Sinus Node as the Primary Pacemaker from the pacemaker cell (P) towards the nonpacemaker cell in the Hierarchy of Pacemakers (NP) through the gap junction channels (curved black arrows and + signs). It also flows in extracellular space from The sinus node is the prototype of normal automaticity the nonpacemaker cell (NP) to the pacemaker cell (P), also and the dominant pacemaker in the normal heart. In down the potential gradient (curved green arrow and + addition, there are other special regions throughout the signs). The addition of positive charges outside the mem- heart where myocardial cells have the normal, intrinsic brane of P and removal of + charges from the inside of the ability to initiate impulses by automaticity. Myocardial membrane caused by the current flow push the membrane cells at these ectopic sites are called latent or subsidiary potential of the pacemaker cell in a negative direction and pacemakers (Figure 1-4). Relationship Between Sinus Node and Latent Pacemakers ¢ 5

pacemakers. The intrinsic rate is the rate at which a cell initiates automatic impulses in the absence of external inhibitory or stimulatory factors such as the autonomic nervous system. The sinus node pacemakers have the fastest intrinsic rates, followed by atrial pacemakers, AV nodal pacemakers, His bundle pacemakers, and then the Purkinje pacemakers in the distal ventricular conducting system. Because the sinus node has the fastest intrinsic rate, the latent pacemakers are excited by propagated impulses from the sinus node and discharge an action potential before sufficient time passes to allow them to depolarize spontaneously to threshold potential and initiate an impulse.

Overdrive Suppression of Latent Pacemakers by the Sinus Node Not only are latent pacemakers prevented from initiating an impulse because they are depolarized by propagating Figure 1-4 Location of pacemakers with normal automaticity (blue stars). electrical activity originating in the sinus node, but also, the SDD of latent pacemaker cells is actually inhibited They include multiple sites in the right and left atria, when the cells are repeatedly depolarized by the impulses the atrioventricular (AV) junction (AV node and His from the sinus node—a phenomenon called “overdrive bundle), and the specialized conducting system of the suppression.” The effect of overdrive suppression can be ventricles (Purkinje system). Pacemaker cells at some of seen when there is sudden failure of the sinus node pace- these sites such as the AV junction and Purkinje system maker to initiate impulses or failure of the impulses to can be identified by a specific histological structure while conduct into the location of the latent pacemaker. Latent most pacemaker cells in the atria usually appear the same pacemaker impulse initiation does not arise immediately as the working myocardial cells with typical contractile but is generally preceded by a period of quiescence. structure and function. Overdrive suppression is exemplified by this period of The latent pacemakers have membrane currents causing quiescence after sudden inhibition of the sinus node pace- SDD similar in many aspects to the mechanism described maker by vagal activity. for the sinus node in Chapter 2 (Figure 2-6). In general, Figure 1-5 shows the ECG during vagal activation by latent pacemaker sites with normal automaticity, like the carotid sinus massage beginning at the “R” in the top trac- sinus node, have cells with an isoform of a specific gene ing, in a normal human subject. The quiescent period prior called the HCN gene (HCN stands for Hyperpolarization- to the appearance of a junctional beat (first impulse in the activated Cyclic Nucleotide-gated). This gene controls the second tracing) reflects the suppressive influence of over- expression of a membrane channel that is involved in the drive suppression exerted on the latent pacemakers, genesis of the pacemaker current. Myocardial cells in atria including this junctional pacemaker, by the dominant sinus and ventricles classified as “working,” i.e., performing the node pacemaker. Several more junctional beats occur prior contractile function, do not normally express pacemaker to reappearance of sinus rhythm after carotid message is ability, although under pathological conditions, they may terminated at the x in the third tracing. The junctional express abnormal automaticity (see Chapter 4). pacemaker is not suppressed by the vagal activation (as are atrial pacemakers and mid AV nodal pacemakers), perhaps Hierarchy of Pacemakers because it is in the lower AV node or His bundle where the Under normal conditions there is a difference in vagus exerts little effect (see Chapter 3). In humans, ven- intrinsic rates among different pacemaker cells in various tricular pacemaker escape is rare after vagal activation, the regions of the heart, which is called the hierarchy of usual site of escape being in the AV junction. CHAPTER Basic Principles of Delayed Afterdepolarizations (DADs) and Triggered Action Potentials 5

riggered activity is the second form of impulse potential and is therefore early with respect to repolariza- initiation listed in the Introduction’s Table i-1. tion. (The blue arrow shows normal repolarization.) Early T “Triggered activity” is the term used to describe afterdepolarizations and the arrhythmias that they cause impulse initiation that is dependent on afterdepolariza- are described in Chapters 7 and 8. tions. It is distinct from automaticity as described in An afterdepolarization does not initiate an arrhythmia Chapters 1–4, which results from spontaneous diastolic until its amplitude is large enough to reach the threshold depolarization. Afterdepolarizations are oscillations in potential for activation of a regenerative inward current membrane potential that follow the primary depolariza- that causes an action potential. In Figure 5-1, Panels A and tion phase (0) of an action potential. Figure 5-1 shows B, this occurs following action potential 2 (second set of the two types of afterdepolarizations that can cause trig- red arrows). These action potentials are referred to as triggered arrhythmias. gered action potentials (action potential 3, in green) and Figure 5-1, Panel A illustrates a delayed afterdepolar- the arrhythmias they cause are called triggered arrhyth- ization (DAD) (red arrow following action potential 1). It mias. Therefore, for triggered activity to occur, at least one is not initiated until repolarization is complete or nearly action potential must precede it (in Panels A and B, the complete and therefore is delayed with respect to repolar- trigger is action potential 2) in contrast to automaticity, ization. DADs and DAD triggered arrhythmias are the which can arise de novo in the absence of prior electrical subjects of this chapter and Chapter 6. By way of compari- activity. (For example, Figure 1-5 shows an escape rhythm son, in Panel B, the second type of afterdepolarization, caused by automaticity after sinus node inhibition, the referred to as an early afterdepolarization (EAD), is shown first impulse arises without an immediately preceding by the red arrow following action potential 1. It is mani- “trigger.”) fested as an interruption in repolarization of the action

Figure 5-1 There are two types of afterdepolarizations. Panel A: Delayed afterdepolarizations (DADs) and DAD- induced triggered action potentials. Panel B: Early afterdepolarizations (EADs) and EAD-induced triggered action potentials. Voltage calibration is at the left with 0 potential indicated; TP, threshold potential (dashed line).

113 Electrophysiological Foundations of Cardiac Arrhythmias: A Bridge Between Basic Mechanisms and Clinical Electrophysiology, Second Edition. © 2020 Andrew L. Wit, Penelope A. Boyden, Mark E. Josephson, Hein J. Wellens. Cardiotext Publishing, ISBN: 978-1-942909-42-2. 114 ¢ Chapter 5: Basic Principles of Delayed Afterdepolarizations (DADs) and Triggered Action Potentials

CHARACTERISTIC APPEARANCE OF DADS AND CELLULAR MECHANISMS OF DADS AND DAD- DAD-TRIGGERED ACTION POTENTIALS TRIGGERED ACTIVITY: THE ROLE OF CALCIUM Figure 5-1, Panel A shows the general features of DADs. DADs and the triggered activity that they cause result An action potential of a myocardial cell at the left (in light from an oscillatory membrane current originally referred

blue, labeled 1) is followed after complete repolarization to as the transient inward current (TI or ITI). This current by a low-amplitude and short-duration depolarization of is distinct from the pacemaker current that causes normal

the membrane potential (in red with red arrow) that is automaticity. A distinguishing feature of ITI is that it is caused by a transient net inward current during diastole. associated with abnormalities in intracellular calcium The afterdepolarization is coupled to and caused by the cycling between the sarcoplasmic reticulum (SR) and previous action potential (see below for a description of myoplasm. This intracellular Ca2+ cycling normally plays the mechanism). The DAD may be preceded by an after- an important role in coupling the action potential to myo- hyperpolarization (black arrow following action potential cardial contraction, a process called excitation-contraction 1), during which the membrane potential becomes tran- coupling in the forward mode. siently more negative than the membrane potential just prior to its initiation. The transient nature of the afterde- Excitation-Contraction (EC) polarization clearly distinguishes it from normal Coupling; Forward Mode spontaneous diastolic (automatic, phase 4) depolarization Owing to the importance of Ca2+ and SR function in the (SDD), during which the membrane potential declines genesis of DAD-triggered arrhythmias, the normal physi- until an action potential is initiated (Figure 1-1, Panel B). ology of EC coupling is first briefly described. Normal EC coupling is sometimes referred to as “forward-mode EC DAD-Triggered Action Potentials coupling,” since excitation (in the form of the action In Figure 5-1, Panel A, the DAD following action potential potential) precedes and causes contraction. Ca2+ enters 2 is larger, and its depolarization (in red, red arrows) the cell during the action potential plateau phase (2) to reaches the threshold potential (TP, dashed horizontal initiate contraction. Abnormalities that cause DADs and line) resulting in a regenerative inward current (Na+ or triggered arrhythmias result from “reverse-mode EC cou- Ca2+, depending on the level of the membrane potential) pling,” since the Ca2+ trigger for contraction from the SR to cause an action potential (action potential 3 in green) precedes excitation that occurs in the form of a DAD. called a triggered impulse. The dashed curve in blue and Figure 5-2, Panels A and B illustrate the normal move- the blue arrow show the time course of the DAD if no trig- ment of Ca2+ back and forth between myoplasm (MYO) gered action potential had been initiated. This emphasizes and sarcoplasmic reticulum (SR) during systole (Panel A) that the triggered action potential arises from a DAD. and diastole (Panel B). DADs do not always reach threshold (following action The SR is a network of tubular membranes depicted as potential 1), so that triggerable cells may sometimes be the red rectangular area in the center of each panel in activated regularly (during sinus rhythm) without becom- Figure 5-2. It is the main store of intracellular Ca2+ (blue ing rhythmically active. The conditions under which they dots). Some of this Ca2+ in the SR is free, and some is reach threshold are described below. A triggered action bound to SR proteins, the most important of which is potential is also followed by a DAD (red trace and arrow calsequestrin 2 (Casq2), the cardiac isoform of the protein. following action potential 3) that may or may not reach Casq2 has a high capacity for binding Ca2+ (50%–70% of threshold. When it does, the first triggered action poten- SR Ca2+ is bound to it), but a low affinity for Ca2+; thus, it tial is followed by a second triggered action potential can readily release free Ca2+ when required. Therefore, (action potential 4 in green), arising from the DAD caused Casq2 is a major determinant of the ability of the SR to by the previous action potential. The blue dashed curve store and release Ca2+, and abnormalities in its function associated with action potential 4 shows the membrane can sometimes cause DAD-triggered arrhythmias. potential had the DAD not reached threshold potential. This process can continue, resulting in a series of triggered action potentials that eventually stop when a DAD does not reach threshold potential. Cellular Mechanisms of DADs and DAD-Triggered Activity: The Role of Calcium ¢ 115

Figure 5-2 Ca2+ cycling between myoplasm (MYO) and sarcoplasmic reticulum (SR) in a ventricular muscle. SR outlined in red, t-tubules outlined in green. CSR; corbular sarcoplasmic reticulum, SR release channels (RyR2) in junctional sarcoplasmic reticulum (JSR). Sarcoplasmic reticulum Ca2+ ATPase-dependent pumps (SERCA: Large black arrowheads). L-type Ca2+ channels: Small red ovals. Na+–Ca2+ exchanger: Light blue oval in sarcolemma. Na+–K+ pump: Dark blue circle. Ca2+ ions: Small blue circles. Panel A: Systole (vertical dashed line above). Panel B: Diastole (vertical dashed line above). Panel C: DAD formation (in diastole). Arrows explained in text.

Free Ca2+ is released from the SR into the myoplasm majority of Ca2+ that interacts with the contractile pro- through calcium release channels in the SR membrane teins in working ventricular and atrial cells, comes from (blue arrows, Panel A) called ryanodine receptors (RyR2). the SR and not directly from Ca2+ flux through the L-type The latter are named as such because they were first dis- channels. The excitation triggers contraction, hence the covered to respond to the plant alkaloid ryanodine that term “forward” EC coupling. opens the channels. The number “2” indicates the pre- Ca2+ release through the RyR2 operated channels (blue dominant isoform of the receptor in cardiac myocytes. arrows) terminates when SR free Ca2+ falls below a thresh- Ca2+ is normally released from the SR during the plateau old level. Ca2+-induced Ca2+ release results in about phase of the transmembrane action potential (Panel A, 40%–60% depletion of Ca2+ from the SR. RyR2 channel vertical dashed line on the action potential). The release is closure may be brought about by an interaction of Casq2 triggered mostly by the entrance of Ca2+ into the cell via with the channel proteins. Casq2 is the putative SR lumi- 2+ ICaL, through the L-type calcium channel (short red nal Ca sensor and inhibits RyR2 channel opening when arrows, and small red ovals). This Ca2+ binds to the exter- Ca2+ is low, causing a temporary state of refractoriness of nal surface of the RyR2 receptors, opening the Ca2+ release the channels after each Ca2+ release, thus preventing Ca2+ channels, a process called Ca2+-induced Ca2+ release. The release during diastole. L-type calcium channels are located in invaginations of Following the Ca2+ release that triggers contraction the sarcolemma forming T tubules that closely abut the (Panel A), the myoplasmic Ca2+ is reduced by two mecha- junctional sarcoplasmic reticulum (JSR) in terminal cis- nisms: (1) resequestration into the SR by calcium pumps ternae to form dyads. Dyads are also formed where SR in the SR membrane (Figure 5-2, Panel B, SERCA, black abuts non-t-tubular, sarcolemmal membranes (top bor- arrowheads) through active transport with energy sup- der). There also may be some net inward Ca2+ movement plied by ATPase, and (2) extrusion from the cell mostly by via the Na+–Ca2+ exchanger operating in the forward the Na+–Ca2+ exchanger in the sarcolemma operating in mode (moves Ca2+ into the cell and Na+ out of the cell) the reverse mode at the negative diastolic potential (note (light blue oval; blue arrow indicates Ca2+, black arrow is reverse direction of the light blue arrow at the blue oval, Na+) during the action potential plateau. Notably, the which represents the Na+–Ca2+ exchanger in Figure 5-2, 116 ¢ Chapter 5: Basic Principles of Delayed Afterdepolarizations (DADs) and Triggered Action Potentials

Panel B). The function of the exchanger in this reverse spontaneously releases some of the Ca2+ back into the mode is described in Chapter 2 in relation to its role in myoplasm through the RYR2 Ca2+ release channels after generating an inward current that contributes to the pace- repolarization and during diastole (curved blue arrows); maker potential. these releases are called calcium sparks since they can be When the Na+–Ca2+ exchanger operates in the reverse detected by fluorescent microscopy. There is a threshold mode, it moves more positive charges (3 Na+, indicated by level of diastolic SR Ca2+ that causes RyR2 channels to black arrow in Figure 5-2, Panel B) into the cell than out open, releasing Ca2+ into the myoplasm in the absence of (1 Ca 2+, blue arrow) at diastolic membrane potentials. The membrane depolarization. This process is called store movement of Na+ is down its concentration gradient and overload-induced Ca2+ release. RyR2 receptors may also generates the energy for moving Ca2+ out of the cell be sensitive to elevated myoplasmic Ca2+, which causes against its concentration and electrical gradients (inside release channels to open. Furthermore, this diastolic Ca2+ 10–4 mM free Ca2+, outside 1.8 mM; inside the cell is nega- release is delayed from the previous major Ca2+ release tive relative to outside the cell, which is positive). The during the action potential plateau that causes contraction concentration gradient for Na+ is maintained by the Na+– because of refractoriness of the release channels that K+ pump that maintains myoplasmic Na+ at low levels (~ results in the occurrence of DADs to be delayed after com- 2–4 mM) (Figure 5-2, Panel B, blue circle, black arrow is plete repolarization. The amount of diastolic Ca2+ release Na+ out of cell in exchange for K+ into cell, yellow arrow). from the SR, as well as the rapidity of the release, is related A small amount of Ca2+ is also extruded from the cell by to the amount of Ca2+ in the SR. The elevated diastolic ATPase-dependent sarcolemmal calcium pumps (black Ca2+ in the myoplasm is the source of the transient inward

arrows at left of the diagram). Under normal circum- (ITI) current that causes DADs (vertical dashed line on stances, myoplasmic free Ca2+ is reduced to a very low action potential above) (described in more detail below). levels during diastole (blue circles) (Figure 5-2, Panel B) The diastolic release of Ca2+ may also be associated with resulting in relaxation. Note the steady level of membrane an after-contraction with minimal force following systole, potential during diastole (vertical dashed line) in Panel B. since the contractile mechanism is also activated. Ca2+ overload may also be associated with an increase in tonic Spontaneous Diastolic SR (diastolic) tension. Calcium Release and DADs The description of Figure 5-2 is an oversimplification of the Ca2+ release process. Rather than the SR being one DADs occur under conditions in which SR Ca2+ levels are functional unit as shown in Panels A–C, it is many func- abnormally elevated called Ca2+ overload. They also occur tional units that are formed because the RyR2 channels if there are abnormalities in RyR2 function caused by are clustered and aligned in a specific anatomical pattern mutations or in acquired pathology (ischemic heart fail- to allow for uniform Ca2+ release from the SR during the ure) that affects RyR2 receptor function. action potential (forward-mode EC coupling). The orderly Figure 5-2, Panel C shows the mechanism for DADs pattern of RyR2 channels on the SR sets up a series of during Ca2+ overload as indicated by the increase in blue potential release sites of Ca2+ in the cell. When overload of circles in Panel C compared to Panels A and B. One cause SR occurs to cause DADs, a wave of Ca2+ propagates from of Ca2+ overload is an increase in Ca2+ entering the cell one ryanodine cluster to another (Ca2+ sparks) through through the L-type Ca2+ channels during action poten- the myocyte. The summated Ca2+ released causes the tials, for example, during sympathetic stimulation. DAD that is shown in Figure 5-2, Panel C. Another cause is a decrease in Ca2+ extrusion from the cell Figure 5-3 shows a ventricular myocyte where a Ca2+ by the Na+–Ca2+ exchanger as occurs with digitalis toxic- wave (indicated by bright fluorescence) has started from ity (described in Figure 5-8). Under these conditions, spontaneous Ca2+ release from the SR (a). This Ca2+ wave there is increased activity of the SR calcium pumps then propagates the length of the cell (b-p). The increased (Figure 5-2 Panel C, SERCA, black arrows). SERCA senses intracellular Ca2+ during the wave is sensed by the Na+– the increased Ca2+ entering the cell (in the myoplasm Ca2+ exchanger, which extrudes the Ca2+ to produce (MYO) and increases its activity to remove Ca2+ from the membrane depolarization as a DAD (see below). This is an MYO into the SR in an attempt to maintain the low dia- example of reverse-mode EC coupling where the increase stolic level of Ca2+ necessary for relaxation. This results in in myoplasmic Ca2+ in the form of a wave, activates Ca2+- Ca2+ “overload” of the SR (blue dots in Figure 5-2, Panel dependent membrane ionic current changes. C). The SR cannot accommodate this overload and Cellular Mechanisms of DADs and DAD-Triggered Activity: The Role of Calcium ¢ 117

Figure 5-3 Cell-wide Ca2+ wave in ventricular myocyte. Images are of a myocyte loaded with a dye that fluoresces with an increase in myoplasmic Ca2+.

In other situations, such as heart failure, ischemic dis- Relationship Between Diastolic Ca2+ ease, or genetic mutations, SR Ca2+ concentration may not and Ionic Currents Causing DADs be elevated and may even be reduced, but alterations in In the presence of SR Ca2+ overload and excessive Ca2+ Ca2+ release channel function may still cause transient release from the SR into the myoplasm during diastole, the abnormally high myoplasmic Ca2+ levels during diastole Na+–Ca2+ exchanger extrudes the elevated Ca2+ from the that causes DADs. These pathophysiological conditions cell in exchange for Na+ (1 Ca 2+ for 3 Na+) generating the are described in more detail in the next chapter on DAD net inward current (I ) causing the DAD (reverse-mode arrhythmias. NCX EC coupling) (Figure 5-2 Panel C, light blue oval, blue 2+ arrow is Ca moving out of cell, black arrow labeled INCX DADs in Purkinje Cells is the inward Na+ current). To reiterate, Ca2+ is actively Purkinje cells of the ventricular conducting system are extruded by the Na+–Ca2+ exchanger against a concentra- more prone to the development of DADs than ventricular tion gradient requiring energy expenditure (blue arrow), muscle, resulting in the Purkinje system being an impor- since free diastolic levels are lower than extracellular con- tant source of triggered arrhythmias. Purkinje cells have a centrations of Ca2+ even when intracellular Ca2+ is microanatomy that is different than ventricular muscle increased in situations where DADs are generated. On the cells depicted in Figure 5-2. In Purkinje cells, t-tubules are other hand, Na+ moves down an electrochemical gradient absent, and Ca2+ entering through the L-type channels (black arrow) from a higher extracellular to lower intra- propagates as a wave from the influx points to the core of cellular concentration. The energy for Ca2+ extrusion the cell to access the RyR2 receptors that are not in direct comes from the movement of Na+ ions down this gradient contact with the sarcolemma, called the corbular sarco- and not the splitting of ATP molecules. The current car- plasmic reticulum (CSR) (Figure 5-2, Panel A). The special ried by Na+ movement causing the DAD is transient and microanatomy of the SR in Purkinje cells with different decreases as Ca2+ at the internal surface of the sarcolem- forms of Ca2+ release channels leads to larger Ca2+ release mal membrane is reduced by the exchanger, hence the 2+ + from the SR and Ca wave propagation. Increased Na nomenclature transient inward current (TI or ITI). INCX is entry during the action potential (both during phase 0 and used synonymously with ITI. The magnitude of INCX is the plateau phase (2) of repolarization) leads to an increase directly related to the Ca2+ that is extruded, and this in in intracellular Ca2+ through the actions of the Na+–Ca2+ turn is directly related to the diastolic Ca2+ concentration exchanger. Increased Ca2+ entry during the long plateau in the myoplasm.

phase compared to atrial and ventricular muscle also In addition to INCX, other inward currents have been enhances occurrence of DADs. Purkinje cells also have a proposed to contribute to DADs. One current is a non-

weaker IK1 than in ventricular muscle. As such, there is less specific membrane current, which was originally outward current at the resting potential to oppose DADs. designated to be the primary TI current. The membrane DADs are also facilitated by weak gap junctional coupling channel of this current was proposed to be Ca2+ sensitive, of Purkinje cells to surrounding myocardium, because opening with elevated diastolic Ca2+, with non-specific Purkinje strands are often separated in bundles from permeability to cations. Since Na+ is the predominant underlying muscle. Normally, muscle cells are tightly cou- cation in extracellular space, it is the primary charge car- pled in three dimensions to surrounding myocardium. As rier of this current. Another possible contributor to the explained in Figure 1-3, such coupling can prevent mem- TI current under certain conditions is a calcium-acti- brane depolarization because of the flow of electrotonic vated chloride current. current during diastole, in this case inhibiting the formation of DADs in muscle cells. 118 ¢ Chapter 5: Basic Principles of Delayed Afterdepolarizations (DADs) and Triggered Action Potentials

ELECTROPHYSIOLOGIC PROPERTIES OF DADS Dependence on Cycle Length AND TRIGGERED ACTIVITY (Rate and Prematurity) The effects of cycle length at which action potentials occur, In general, the magnitude of DADs as well as coupling on DADs and DAD-dependent triggered activity differ interval to the preceding action potential are related to the from their effects on automaticity. These differences pro- diastolic Ca2+ levels and the rapidity of Ca2+ release from vide a basis for distinguishing triggered arrhythmias from the SR. Therefore, events that change the diastolic Ca2+ automatic arrhythmias and for using electrical stimulation levels and speed of release affect the occurrence and char- protocols for identifying triggered activity as a cause of acteristics of triggered arrhythmias. arrhythmias. Some of the key differences are as follows: Dependence on Action Potential Characteristics ¢ Automaticity of ectopic pacemakers is not initiated by an increase in rate (decrease in cycle length) of One of the factors that controls the size of DADs and the the dominant (sinus node) pacemaker or by propensity for occurrence of triggered activity is the char- electrical stimulation and is transiently suppressed acteristics of the action potentials that precede them. by overdrive (overdrive suppression).

¢ Effects of Action Potential Duration DADs are enhanced by an increase in rate (decrease in cycle length) at which triggerable cells are The duration of the action potential (APD)—time stimulated. Therefore, triggered arrhythmias can be from depolarization to complete repolarization—influ- initiated by decreasing the cycle length and triggered ences the intracellular and diastolic Ca2+ levels that cause activity can be accelerated by overdrive (overdrive DADs. Ca2+ enters the cell during the plateau phase of the acceleration). action potential via ICaL, which inactivates as repolarization proceeds to levels more negative than around –60 mV. Therefore, shortening the action potential duration Effect Rate on DAD Amplitude, Coupling

decreases ICaL, which suppresses DADs while lengthening Interval, and Triggered Activity it increases ICaL and enhances DADs. Changes in action This effect of rate (or triggering cycle length) is illus- potential duration can be brought about by changes in the trated in Figure 5-4, which is a diagram of action repolarizing IK current (see Figure 7-2 for description of potentials recorded from a cell with DADs. At the left in repolarizing membrane currents), a decrease of which each panel, the first three action potentials (in black) prolongs APD, and an increase of which shortens APD. A occur at a cycle length of 1000 ms. The small black number of drugs can alter IK, thereby influencing DADs. arrows point out the DADs. Such subthreshold DADs For example, Class IA drugs (Vaughan Williams classifi- might occur during sinus rhythm and not be noticed on cation) that decrease IK can increase DAD amplitude by the ECG. lengthening APD and cause triggered activity in the In Panel A, the cycle length decreases to 800 ms (blue experimental laboratory and possibly in patients. action potentials) and DAD amplitude increases (blue arrow), but does not reach the threshold for initiating a Effect of Initial Membrane Potential triggered action potential. In the diagram the cycle length The amplitude of DADs is dependent on the level of is decreased for 10 sec (double black vertical bars indicate membrane potential at which they arise. Although they break in time scale; only last 3 sec are shown to the right may occur in cells with normal resting potentials of of the bar) as might occur with an increase in sinus rate or ~ –80 to –90 mV, amplitude can increase as membrane during pacing. potential becomes less negative. Part of this effect may In Panel B, the cycle length is decreased from 1000 ms

result from a decrease in outward (IK1) current, which (black action potentials at left) to 600 ms (blue action occurs during membrane depolarization, and part may potentials). There is an increase in the amplitude of the

result from an increase in ITI current (INCX). DADs can DADs (blue arrow) that causes one to reach threshold (red occur at low diastolic membrane potentials where nor- arrow), initiating a triggered action potential (red arrow

mal automaticity does not occur because If is inactivated and action potential). The DAD following the triggered (see Figure 4-3). Therefore, DADs may occur in disease- action potential does not reach threshold (red arrow at the induced depolarized cells as well as cells with normal far right) and triggered activity stops after one impulse. levels of membrane potential. This is analogous to an increase in heart rate or pacing rate triggering a premature impulse. Electrophysiologic Properties of DADs and Triggered Activity ¢ 119

Figure 5-4 Effects of rate expressed as cycle length on DADs and triggered activity.

In Panel C, the cycle length decreases from 1000 ms The relationship between stimulus cycle length (labeled (black action potentials at left) to 400 ms (blue action as activation or triggering cycle length, Act/Trig CL) and potentials). The DAD amplitudes increase even more DAD amplitude and coupling interval is shown in Figure (blue arrow). A DAD reaches threshold (red arrow) to 5-5. The DAD amplitude is shown to increase as cycle trigger an action potential (in red) that is followed by a length decreases (red circles and line). series of triggered action potentials since the DAD after each action potential also reaches threshold potential (dashed red trace indicates DAD of the triggered action potential; green vertical bars indicate a break in the time scale of 10 sec). Triggered activity stops when a DAD fails to reach threshold potential (red arrow at the far right). This is analogous to an increase in spontaneous or stimulated heart rate triggering a tachycardia. In Panel D, cycle length decreases from 1000 ms (black action potentials at the left) to 300 ms (blue action potentials). The DAD amplitude is even larger (blue arrow). A DAD reaches threshold (red arrow), initiating a triggered action potential (red) that is followed by a DAD (dashed trace) that also initiates a triggered action potential. Each triggered action potential triggers the next one through the same mechanism. After a period of 10 sec—the break in time scale indicated by the green vertical bars—triggered activity terminates, with the last triggered impulse Figure 5-5 Effects of stimulus cycle length expressed as activation or triggering cycle length (Act/Trig CL, abscissa) on DAD amplitude in followed by a DAD that does not reach threshold (red mV (right ordinate, red line) and DAD coupling interval (green and blue arrow at the far right). Panel D also illustrates that the rate lines). of triggered activity is faster and duration is longer when initiated at a shorter cycle length. 120 ¢ Chapter 5: Basic Principles of Delayed Afterdepolarizations (DADs) and Triggered Action Potentials

The direct relationship between stimulus cycle length In Figure 5-6, Panels A–D, action potentials at the left (Act/Trig CL) and coupling interval of the DAD or first (shown in black) are occurring at a cycle length of 1000 ms triggered impulse to the action potential upstroke (phase and are associated with DADs that are subthreshold 0) is also shown in Figure 5-5 (blue line). This was also (black arrows). In Panel A, a premature action potential at shown in Figure 5-4 where the coupling intervals between a coupling interval of 800 ms (in blue) is followed by a the DAD and the preceding action potential decrease as DAD with a larger amplitude (blue arrow) that is still sub- the cycle length decreases. As a result, the coupling inter- threshold. Likewise, in Panel B, the premature action val between the first triggered action potential and the potential at a coupling interval of 600 ms (in blue) is fol- preceding triggering action potential decreases (horizon- lowed by a DAD with a larger amplitude than in A (blue tal red bars in Figure 5-4, Panels B–D) as the stimulus arrow) but which is also subthreshold. In Panel C, the cycle length decreases. The direct relationship is caused by premature action potential (in blue) at a coupling interval two factors. One is that the peak of the DAD occurs of 500 ms is followed by a DAD that does reach threshold sooner after complete action potential repolarization (blue arrow) for triggering an action potential (in red), because of increased speed of Ca2+ release from the SR as which is then followed by a short series of triggered action indicated by the green circles and line. The second is that potentials (in red) that terminates with a subthreshold the APD decreases as the cycle length decreases, which is DAD (red arrow at the far right). In Panel D, at a still the usual effect of cycle length on APD owing to an shorter premature coupling interval of 300 ms, the DAD

increase in IP and IK, outward currents that accelerate following the premature action potential (in blue) also repolarization (described in Figure 7-7). (The blue line reaches threshold (blue arrow) to trigger a longer period of represents the combination of the two factors). triggered action potentials (in red), (vertical green bars in Panel D indicate a break of 10 sec in the time scale) which Single Premature Impulses as Triggers terminates with a subthreshold DAD (red arrow at the far A decrease of even a single cycle length in the form of right). (Whereas the figure shows a longer period of trig- a premature impulse also increases the amplitude of gered activity initiated at a shorter coupling interval, this DADs and decreases the coupling interval and can trigger does not always occur.) impulse initiation as illustrated in Figure 5-6.

Figure 5-6 Effects of a decrease in a single cycle length (a premature impulse) on DADs and triggered activity. Electrophysiologic Properties of DADs and Triggered Activity ¢ 121

Similar to the direct relationship between stimulation stimulation), where premature stimulation is usually more rate (cycle length) and coupling interval of the DAD effective in initiating arrhythmias than overdrive (see described in Figure 5-5, the coupling interval of the DAD Chapter 9 for an explanation). The higher level of diastolic and/or the first triggered impulse to the single premature Ca2+ during more rapid rates of pacing accounts for the impulse decreases as the premature cycle length decreases. observation that it is easier to initiate triggered arrhyth- This relationship is shown in Figure 5-6. The blue hori- mias by premature activation during more rapid pacing zontal bar below the action potentials is the coupling rates, since DAD amplitude is closer to threshold. Slow interval of the premature impulse which decreases from rates often potentiate the initiation of reentry, but in some Panels A–D. The red horizontal bar is the coupling inter- situations, rapid rates also favor induction of reentry by val of the peak of the DAD of the premature impulse (A, premature impulses. B) or first triggered impulse (C, D), which also decreases. As with the effects of rate, shortening of the coupling Triggered Activity Rate and Duration interval of the DAD and first triggered impulse results The rate of triggered activity is governed by the time it from shortening of APD and shortening of the interval takes for a DAD to depolarize the membrane potential between peak DAD amplitude and complete repolariza- from the maximum diastolic potential (MDP) to the tion of the preceding action potential. threshold potential for initiating an action potential. The effects of rate (cycle length) and premature Therefore, rate is dependent on the relationship between impulses on the amplitude and coupling interval of DADs 2+ MDP, rate of DAD depolarization, and threshold potential is related to their effects on the amount of Ca in the (similar to rate of automaticity; see Figure 1-2). APD also myoplasm during diastole. As described above (see Figure 2+ influences triggered activity rates, with faster rates associ- 5-2), Ca enters the myocardial cell during the plateau ated with shorter action potential durations. phase of the action potential and is taken up into the SR, as well as causing SR Ca2+ release. Thus, a greater number of action potentials as occurs with an increase in rate/ Warm Up decreased cycle length results in more Ca2+ entering into The rate of DAD depolarization increases and APD the cell and the SR, as well as more Ca2+ being released shortens progressively during the initial impulses of trig- from the SR during diastole. The elevated diastolic Ca2+ gered activity. Because of the decreased cycle length of the first triggered impulse related to the decreased DAD cou- that generates the INCX or ITI current and the DAD is increased. The rate of release of Ca2+ from the SR also pling interval, the second triggered impulse will also have increases as SR Ca2+ increases, causing DADs to occur a decreased cycle length because of the decreased coupling 2+ earlier relative to repolarization. interval of the preceding DAD, resulting in more Ca Related clinical observations. Although the relation- entering the cell, increasing the DAD amplitude and ship between the initiation of triggered activity and decreasing the coupling interval of the next triggered 2+ preceding cycle length described above can often be impulse. The increased Ca causes a gradual decrease in observed in clinical studies (see Chapter 6), the direct triggered cycle length (called “warm up”) until a steady relationship between activation cycle length and coupling state is reached (Figures 5-4 and 5-6, Panels C and D). interval of the first triggered impulse is not always Another factor that may contribute to the decrease in observed. The increase in rapidity of SR Ca2+ release with cycle length during triggered activity is a slow and gradual decreased cycle length that underlies this relationship may depolarization of the MDP (membrane potential becomes reach a maximum beyond which no further increase less negative) moving MDP closer to the threshold poten- occurs. The cycle length at which this occurs varies under tial. This depolarization can result from accumulation of + different conditions and in different tissues. It might K just outside the cell membrane (coming from the move- + sometimes occur at relatively long cycle lengths, and as a ment of K from intra- to extracellular space carried by result, shortening the cycle length at which tachycardia is the repolarizing IK), if circulation is not sufficient to rap- initiated in clinical stimulation protocols will not produce idly wash it away. the expected decreased coupling interval. An increase in rate initiating triggered activity causes Duration and Termination more Ca2+ release than a single premature activation, As described above, the rate of triggered activity may accounting for the more likely initiation of triggered increase and the duration of the period of triggered activ- arrhythmias by overdrive than by premature activation. ity become longer as the triggering cycle length decreases. This contrasts with the characteristics of reentry (the These features are also related to the amount of Ca2+ other arrhythmogenic mechanism initiated by entering the cell during the triggering cycle length, with 122 ¢ Chapter 5: Basic Principles of Delayed Afterdepolarizations (DADs) and Triggered Action Potentials

2+ more Ca entering at shorter cycle lengths. This relation- before because of persistent increased IP. This effect gradu- + ship can sometimes be seen in clinical studies and ally diminishes as IP returns intracellular Na towards provide evidence for DAD-triggered arrhythmias as normal. As a result, another episode of triggered activity described in Chapter 6. cannot quickly occur, since the hyperpolarized membrane

Triggered activity can be sustained or paroxysmal. potential and increased outward IP prevent DADs from Before terminating spontaneously, it may gradually slow reaching the threshold potential. With time, as IP dimin- (Panel D in Figure 5-4 and Figure 5-6). The slowing and ishes, triggered activity can again be induced. This property termination results from an increased activity of the Na+– is sometimes observed in clinical studies on triggered + K pump and outward IP. In cells with high (more negative arrhythmias in which another arrhythmic episode cannot –70 to –90 mV) levels of membrane potential, Na+ enters be immediately initiated after initiation and termination of during phase 0 of each triggered action potential and is a triggered arrhythmia by electrical stimulation. + + pumped out of the cell by the Na –K pump generating IP as described in Figure 1-6. As the triggered rate speeds up, Effects of Overdrive Stimulation + the amount of Na entering the cell increases. The increase During Triggered Activity in outward I current opposes the inward current causing P The factors that govern rate and spontaneous termina- the DADs, eventually decreasing the rate and amplitude of tion of triggered activity are also involved in the response the DADs, thereby slowing the rate of the triggered action of ongoing triggered activity to overdrive stimulation. potentials. In addition, I moves membrane potential in a P These effects are important when considering the effects of negative direction, gradually moving maximum diastolic overdrive on clinical triggered arrhythmias (Figure 5-7). potential of the DAD further from the threshold for activa- Figure 5-7 shows a diagram of triggered action tion of a triggered action potential until triggered activity potentials after a long period of triggered activity at the stops when the peak DAD amplitude does not reach this left in black. During each action potential, Na+ (blue threshold potential (Figure 5-4, Panel D, and Figure 5-6, arrow) and Ca2+ (green arrow) enter the cell, and K+ Panel D, red arrows at the right). In situations in which the (red arrow) leaves the cell. The Na+–Ca2+ exchanger Na+–K+ pump is not able to generate sufficient I such as in P (green oval) generates the TI current by extruding 1 digitalis toxicity where the pump is partially inhibited, Ca2+ for 3 Na+ (I downward blue arrow) causing the other mechanisms related to Ca2+ overload effects on ion NCX, DADs perpetuating triggered activity. Na+–K+ pump channels contribute to termination of triggered activity. activity (blue circle) extrudes 3 Na+ (upward blue After the termination of triggered activity, membrane arrow) in exchange for 2 K+ (downward red arrow). potential may be more negative (hyperpolarized) than

Figure 5-7 Triggered arrhythmia response to overdrive. Electrophysiologic Properties of DADs and Triggered Activity ¢ 123

The red action potentials show a period of overdrive, Parasympathetic Suppression + 2+ during which there is increased Na and Ca entering and The parasympathetics (vagus nerve) can suppress + K leaving the cell during the action potentials. At the end DADs and triggered activity in atrial, A-V nodal and ven- of the period of overdrive (action potentials are black tricular tissues (Purkinje fibers and ventricular muscle). + 2+ again), there is increased activity of the Na –Ca In atrial and A-V nodal cells, acetylcholine released from exchanger (larger green oval) because of the increased parasympathetic nerve endings acts on the M subtype of 2+ 2 Ca that entered during overdrive, enhancing INCX and muscarinic receptors to slow and terminate triggered + + TI, causing overdrive acceleration. The Na –K pump activity. This effect is brought about through a G protein- activity also is increased (larger blue circle), generating + mediated increase in outward K current through KACh more outward IP that eventually overcomes the increased channels. The increase in outward current opposes the inward INCX, causing the DADs to become smaller, and inward current during DADs (decreases net inward cur- hyperpolarizing the membrane potential until triggered rent) that decreases their amplitudes and makes the activity stops when a DAD fails to reach threshold poten- membrane potential more negative, preventing DADs tial (arrow at the far right). from reaching threshold potential. Acetylcholine also Thus, at an appropriate overdrive rate, the overdrive is 2+ decreases inward L-type Ca current (ICaL) by suppress- followed by overdrive acceleration, then slowing, and ing adenylate cyclase to reduce intracellular Ca2+ loading. finally termination. Slower overdrive rates may only cause Although ACh does not increase a KACh channel current acceleration followed by a return to the pre overdrive cycle in ventricular tissues, it can prevent the increase in cyclic length. Faster overdrive rates may cause immediate termi- AMP (cAMP) that underlies the formation of DADs + + nation. As for spontaneous termination, when the Na –K under sympathetic stimulation by the process of accentu- pump is partially inhibited by digitalis toxicity (see Figure ated antagonism described in Chapter 1. 5-8), IP is less important in overdrive termination and 2+ increased intracellular Ca effects on ion channels may DADS Caused by Digitalis Toxicity be more important. Digitalis is used as adjunct therapy in heart failure and for Effects of the Autonomic Nervous System rate control in atrial fibrillation. In addition to enhancing automaticity (Chapter 1), the drug can cause arrhythmias Sympathetic Stimulation due to triggered activity (described in detail in Chapter 6). The sympathetic nervous system is an important fac- The mechanism for the arrhythmogenic effect of digitalis tor controlling the initiation and rate of DAD-dependent to cause DADs and triggered activity is linked to the triggered activity. Sympathetic activation or β1-adrenergic mechanism for its positive inotropic effects in the atria agonist drugs can result in the appearance of DADs in and ventricles. Digitalis binds to high-affinity isoforms of atrial, specialized ventricular (Purkinje) and ventricular the Na+–K+ pump to block pump activity. In therapeutic muscle cells and likely A-V nodal cells (Figure 6-1). When amounts, only a small fraction of pumps in the sarco- DADs are already present, sympathetic activation lemma are blocked, with a consequent increase in + + increases the amplitude and rate of depolarization of intracellular Na concentration. The increase in Na con- DADs, decreases their coupling interval and increases the centration throughout the cytoplasm (referred to as the rate and duration of triggered activity. bulk phase) is very small, but the increase in Na+ concen- The sympathetic nervous system exerts its effect on tration in restricted intracellular spaces (an intracellular DADs through the effects of norepinephrine to increase region that is not in equilibrium with the bulk phase) can Ca2+ entry into cells through the L-type Ca2+ channels. be substantial. Such a restricted space important for digi-

β1-receptor activation by catecholamines results in phos- talis effects on contractility and arrhythmogenesis is phorylation of the L-type Ca2+ channels, which increases diagrammed in Figure 5-8. 2+ opening of the channels and L-type Ca current, ICaL. Figure 5-8 illustrates that the restricted space (separated RyR2 receptors in SR Ca2+ release channels are also from the bulk phase of the myoplasm) where there can be a phosphorylated, increasing their release activity. substantial increase in Na+ concentration, is located in the Norepinephrine also increases activity of the calcium regions where the terminal cisternae of the junctional SR pump (SERCA) to move more Ca2+ into the SR, because (JSR) abut the sarcolemma membrane. Here, there may be 2+ phosphorylation of the protein phospholamban removes co-localization of L-type Ca channels and ICaL (red ovals its inhibitory effects on the pump. and arrow), high affinity Na+–K+ pumps (large dark blue circle), Na+–Ca2+ exchangers (large light blue oval) and RyR2 receptors, all of which have a role in DAD formation.

CHAPTER

Basic Principles of Reentry: Altered Conduction and Reentrant Excitation 9

Overview and General Principles The Ring Model The basic principles underlying reentrant excitation are shown in a schematic diagram of a ring of excitable car- Altered impulse conduction represents the second major diac muscle with a central inexcitable region (in black) in category of arrhythmia mechanisms (Introduction, Table Figure 9-1. The ring is a model of an anatomical reentrant i-1). One means whereby altered impulse conduction circuit—an anatomically fixed pathway around an ana- results in the occurrence of arrhythmias is the manifesta- tomical obstacle. Conducting impulses are indicated by tion of latent pacemakers that occurs when sinoatrial the blue arrows, with the arrowhead showing the leading (S-A) or atrioventricular (A-V) block is present (described edge or head of the propagating impulse (the wave front), in Chapters 1-4. Altered impulse conduction also causes and the blue segment of the tail of the arrow indicating reentrant excitation (reentry), a mechanism for arrhyth- inexcitable myocardium (the effective refractory period) mias that does not depend on the generation of de novo that the impulse has just excited. In Figure 9-1, the red impulses, as occurs with the mechanisms of automaticity segment of the tail indicates partially recovered myocar- and triggered activity. dium during the relative refractory period. (Note that in other figures, e.g., Figure 9-14, the length of the arrow tail REQUIREMENTS FOR REENTRY does not indicate the inexcitable or partially recovered While the underlying detailed mechanisms of clinical myocardium as it does in Figure 9-1. Where not otherwise reentrant arrhythmias are more complicated, a simple indicated, the entire arrow simply represents the direction ring model of reentry describing impulse movement in a of impulse propagation.) circular pathway (circus movement) provides the foundation for these more complicated concepts.

Figure 9-1 Model of reentry in an anatomical circular pathway. The diagrams show snapshots of the sequence of impulse propagation (arrows) over a period of time (across the row from A–E) after initiation at the black dot in Column A1–A3.

197 Electrophysiological Foundations of Cardiac Arrhythmias: A Bridge Between Basic Mechanisms and Clinical Electrophysiology, Second Edition. © 2020 Andrew L. Wit, Penelope A. Boyden, Mark E. Josephson, Hein J. Wellens. Cardiotext Publishing, ISBN: 978-1-942909-42-2. 198 ¢ Chapter 9: Basic Principles of Reentry: Altered Conduction and Reentrant Excitation

Figure 9-1, row 1 diagrams bidirectional impulse con- (brown-shaded area of Panel A2), also known as unidirec- duction. Snapshot A1 illustrates impulses initiated at a tional block. Electrophysiological mechanisms for point (black dot), propagating away from the site of origin permanent unidirectional conduction block are described in opposite directions in the ring. During the time period later in Figures 9-15 and 9-16. between A1 and B1, the two impulses reach the distal side of the ring where they collide (blue arrows in snapshot Importance of the Wavelength of the B1). The impulses die out because they are surrounded by Conducting Impulse in Reentry tissue that has just been excited and that remains refrac- In addition to unidirectional conduction block, for tory for a period of time that outlasts the time for reentry to occur, the impulse that is conducting around propagation. This pattern is somewhat analogous to an the circuit must always find excitable tissue in the direc- impulse originating in the sinus node (black dot) that tion in which it is propagating, i.e., the tissue that was dies out after exciting atria and ventricles because it is excited in the previous transit around the ring must have surrounded by effectively refractory myocardium and recovered excitability. In order for this requirement to be runs into the inexcitable fibrous annulus after depolar- fulfilled, the conduction time around the ring must be ization of the ventricles. After a period of quiescence, longer than the effective refractory period of the myocar- (C1), a new impulse must be initiated for subsequent dium that comprises the ring. For purposes of describing activation (at the black dot) (D1 and E1), analogous to the the mechanism for reentry, the concept of wavelength of next sinus impulse. the conducting impulse can be used. A definition of “wavelength” (λ is the distance traveled Unidirectional Conduction Block by the depolarization wave during the time the tissue Under Special Conditions restores its excitability sufficiently to propagate another Diagrams in row 2, A2–E2, show how the propagating impulse. Thus, wavelength (λ) = conduction velocity (θ) × impulse can persist to reexcite, i.e., reenter, regions it has effective refractory period (ERP). In Figure 9-1, A2–E2, already excited. the length of the blue arrow (from arrowhead to the end of In snapshot A2, excitation again is initiated at the black blue tail) is the wavelength of the conducting impulse, the dot. By temporarily causing conduction block in the right- time between the head of the wavefront and recovery of to-left (clockwise) direction near the site of stimulation (at excitability, even though recovery is not complete. The the brown rectangle), excitation is induced to progress in end of the blue tail signifies the functional refractory only one direction, to the right (counterclockwise), around period, which is the earliest time that an impulse can the ring (blue arrow). Mechanisms for transient block in propagate following a prior excitation. The myocardium the in situ heart that cause clinical arrhythmias are in front of the arrowhead in Panels C2 to E2 has recovered described in Figures 9-14, 9-15, and 9-16. After an impulse as indicated by the unshaded region. This requirement is conducting in one direction around the ring (B2–E2 that conduction around the circuit must take long enough show snap shots of the impulse at progressive time peri- to allow recovery from the effective refractory period can ods), if conduction is restored in the region of the block, be expressed in terms of the relationship between the the impulse can then return to its site of origin and reexcite wavelength (λ) of the conducting impulse (the length (reenter) tissue it previously has excited (D2 and E2). Thus, from blue arrowhead to end of blue tail) and the length of the block is unidirectional (only clockwise) and the impulse the reentrant pathway (path length, l). In other words, the can conduct counterclockwise. The ring forms a reentrant wavelength (λ) of the reentrant impulse must be shorter pathway or circuit. The impulse can also continue to circu- than the length of the pathway (λ < l). In Figure 9-1, A2– late, repeating the pattern of snapshots B2–E2. This simple E2, the wavelength is significantly less than the path model demonstrates that for reentry to occur, a region of length, leaving a large part of the circuit excitable, enabling block must be present, even if only transiently (the brown it to be reexcited by a propagating wavefront. rectangle in Panel A2). The block is necessary to launch Spatial and temporal excitable gaps. The excitable propagation of the impulse in one direction and to prevent region of the circuit forms the spatial excitable gap which early excitation of the pathway (at the left side of the ring) is the distance occupied by the excitable region at any that eventually becomes the return pathway that the moment in time. The spatial excitable gap is comprised of impulse then uses to reenter the region it reexcites. In the a partially excitable gap where myocardium is still rela- ring model shown in Figure 9-1, identical circular move- tively refractory (curved red line), and a fully excitable gap ment would occur if, instead of transient block, permanent where myocardium has completely recovered excitability conduction block occurred in the clockwise direction (unshaded region). Requirements for Reentry ¢ 199

In clinical studies to evaluate the excitable gap during a reentrant tachycardia, only a temporal excitable gap or excitable period can be identified, which is the time interval of excitability between the head of activation of one impulse and the tail of refractoriness of the prior impulse. This will be described in detail in Chapters 10, 11, and 12 on clinical reentrant arrhythmias. The temporal excitable gap is measured by stimulating premature impulses, usually outside the circuit, and observing the resetting response that results from the premature impulse entering and conducting around the circuit (described in detail in Figure 9-27, and Figure 9-28). The spatial excitable gap cannot usually be evaluated, since it would require stimulating at multiple sites within the circuit to evaluate how much of the circuit is excitable, which cannot usually be done in clinical studies. Figure 9-1, row 3 A3–D3, diagrams a situation where the wavelength is longer than the path length (θ > l), pre- cluding reentry, since there is no excitable gap. Snapshot A3 shows initiation of conduction in one direction (counterclockwise) because of the region of transient block in the clockwise direction (brown-shaded region). Conduction velocity is much more rapid so that by Snapshot B3, the impulse has almost completed its transit around the circuit without providing enough time for recovery of excitability, indicated by the long length of the blue arrow. In C3, the wavefront (arrowhead) collides with its refractory tail and blocks. The reentering impulse dies out (D3). In general, for reentrant circuits of the same length, Figure 9-2 Panel A shows an action potential as it is traditionally the excitable gap decreases as the wavelength increases, displayed. Panel B (1, 2, 3) shows how much space the action potential waveform occupies (the wavelength). either because of an increased conduction velocity or an increased effective refractory period. This is one reason Figure 9-2, Panel B shows a different way of depicting that reentrant circuits causing fast tachycardias usually the action potential; it shows the action potential in space have small excitable gaps when the increase in the wave- as it propagates along a 7-cm long muscle bundle from left length is caused by a faster conduction velocity. to right. The muscle bundle depicted here represents a Relation of wavelength to the propagating action circular reentrant pathway that has been cut through and potential. Figure 9-2 pictures the wavelength of the con- laid out in a straight line—the two ends, a and b, were ducting impulse as it relates to a propagating normal attached before cutting. In this representation, the voltage ventricular muscle action potential with typical voltage- scale is still on the ordinate, but the abscissa represents dependent recovery of excitability. Panel A shows the time distance or space in cm (in blue at the top of the panel). course of a ventricular muscle action potential. The volt- The initial phase 0 of the action potential is now at the age scale is on the ordinate. Time is indicated by the red right, leading the movement of the depolarizing wavefront arrow below it on the abscissa, beginning at 0 and ending (blue arrowhead) as it conducts over the bundle. at 400 ms. The depolarization phase 0 occurs first at time At the time shown in Panel B1, action potential 1 has 0, followed by repolarization phases 1, 2, and 3, which end propagated for about 4.5 cm along the bundle. Action at time 400 ms. The effective refractory period ends at the potential repolarization phases 1–3 trail the leading vertical dashed green line (300 ms) followed by the relative phase 0. The effective refractory period is between phase refractory period. The conduction velocity of the action 0 and the vertical dashed purple line, showing the spatial potential is not displayed in this kind of representation, extent of the tissue that is refractory in the muscle bun- and changes in velocity do not influence the appearance dle. Repolarization to the end of the effective refractory of the action potential as long as phase 0 and repolariza- period takes 0.3 sec. The wavelength of the action poten- tion time are not altered. tial is the space occupied by the action potential between 200 ¢ Chapter 9: Basic Principles of Reentry: Altered Conduction and Reentrant Excitation

phase 0 and the end of the effective refractory period. It excitable. There is a large fully excitable gap (dashed line) is dependent on both the conduction velocity (10 cm/sec as well as a partially excitable gap (red line). in B1) and time for repolarization to the end of the effec- Effect of variable conduction velocity and repolar- tive refractory period (0.3 sec in B1) and is the product of ization. At the beginning of the chapter, Figure 9-1 these two values (wavelength = 3 cm). The extent of the represents a simple model of a reentrant circuit where the wavelength is also shown by the blue arrowhead to end of wavelength remains constant during transit of the impulse blue arrow tail that corresponds with phase 0 of the around the circuit because conduction velocity and repo- action potential to the end of the effective refractory larization remain constant. If conduction velocity and period. In muscle cells in diseased regions, the effective refractory period vary from site to site in a circuit, the refractory period may extend further, beyond complete wavelength will change during propagation of the reen- repolarization, called “postrepolarization refractoriness” trant impulse, as diagrammed in Figure 9-3. Specific (see Figure 9-7). Nevertheless, the concept of wavelength examples of clinical arrhythmias that show these features is still the same. are described in subsequent chapters. The impulse as represented by the wavelength does not occupy the entire muscle bundle, there is a region in front of it (dashed line in front of arrowhead) which has not yet been excited and is still completely excitable. This represents the fully excitable gap of the reentrant circuit. There is also a relatively refractory region between the end of the effective refractory period and complete repolarization at the left of the bundle, which represents a partially excitable gap (red segment of arrow tail). Figure 9-3 Reentry in a circuit in which wavelength changes in In Panel B2, action potential 2 shows what happens to different regions of the reentrant pathway. the wavelength when conduction velocity of the impulse Figure 9-3 diagrams the propagating wavefront (blue increases to 17 cm/sec but the time for repolarization arrowheads) and the effectively refractory (blue) and par- remains at 0.3 sec (factors that control conduction velocity tially refractory (red) tail, at three different positions (A, are described later in this chapter). Phase 0 depolarization B, and C) in a reentrant circuit. Conduction velocity is moves more rapidly from left to right down the length of slower in the segments of the circuit in Snapshots A and the muscle bundle, propagating about 7 cm at the time C, resulting in a shorter wavelength (blue arrowhead to shown. The impulse propagates a longer distance during blue tail) than in Snapshot B, where conduction velocity is the 0.3 sec required for repolarization to the end of the rapid causing a long wavelength (blue arrowhead to blue effective refractory period. As a result, the wavelength of tail). Therefore, the spatial duration of the fully excitable the impulse expands to approximately 5 cm; conduction gap when the propagating impulse is at the position in B, velocity of 17 cm/sec × 0.3 sec = 5.1 cm. There is no fully is much smaller than when the impulse is at the positions excitable gap (no dashed line ahead of the impulse). in A and C. However, the average wavelength must still be (Remember that the fiber bundle in the figure represents a less than the path length. circular reentrant pathway: the end of the bundle “b” con- nects to the beginning of the bundle “a”.) The extent of the wavelength is also shown by the blue arrowhead to blue Location and Form of Reentrant Circuits arrow tail which coincides with the action potential from Reentrant circuits can be located almost anywhere in phase 0 to the end of the effective refractory period. Part of the heart and can assume a variety of sizes and shapes. the bundle indicated by the red line, is relatively refractory The size and location of an anatomically defined reentrant forming a partially excitable gap. The impulse can still circuit remains fixed and results in what may be called conduct around the circuit in this partially excitable gap. “ordered reentry.” Anatomical circuits have a central ana- Panel B3, action potential 3 shows the effects of reduc- tomical obstacle (Figures 9-1) that prevents the impulse ing the duration of the action potential by accelerating from taking a “short cut” that would preexcite a segment repolarization to 0.2 sec. The conduction velocity is 10 of the pathway and stop reentry. The circuit may also be cm/sec, the same as in B1. Now, as the impulse moves over functional and its existence, size and shape determined by the same distance as in B1, the more rapid repolarization electrophysiological properties of the cardiac cells rather shortens the wavelength of the impulse to 2 cm so that it than an anatomically defined pathway. The size and loca- occupies less of the bundle (blue arrowhead to end of blue tion of reentrant circuits dependent on functional tail), leaving an extensive region of the bundle that is fully properties can be ordered but also may change with time Necessary Electrophysiological Properties for Reentry ¢ 201 leading to random reentry. Nevertheless, the relationship Effects of the Depolarization Phase (0) of between path length and wavelength still apply. Reentrant the Action Potential on Conduction circuits can also be a combination of anatomical and Important features of transmembrane action poten- functional components. The different kinds of reentry are tials that govern the speed of propagation are (1) the described in Figures 9-17 to 9-21. amplitude of the action potential (positivity of phase 0) The model of the reentrant circuit diagrammed in which reflects the magnitude of the inward depolarizing Figure 9-1 is modified for the description of clinical current, and (2) the rate at which phase 0 depolarizes the arrhythmias, the modification being dependent on the . cell (dv/dtmax of phase 0 in volts/s, also expressed as Vmax), location of the reentrant circuit. which indicates the speed at which the inward current reaches maximum intensity. Reduction of these parame- NECESSARY ELECTROPHYSIOLOGICAL ters slows conduction. Figure 9-4, Panels A–C show the PROPERTIES FOR REENTRY mechanism for normal rapid conduction and the effects of . reducing the amplitude and dv/dt (V ) of phase 0, in The basic electrophysiological properties that facilitate max max a simple model of linear conduction through a strand of reentry are slow conduction, unidirectional conduction three myocardial cells (labeled 1, 2, and 3) with phase 0 of block, and time for recovery of excitability. the action potentials dependent on INa. The cells are physi- cally connected by the intercalated disks and electrically Slow Conduction of the Propagating Wavefront connected internally by channels in gap junctions that For reentry to occur, the conducting impulse must be reside in the disks (in yellow). The model does not take delayed sufficiently in its transit through the reentrant into account microscopic discontinuities formed by the pathway to allow regions in front of it to recover excit- gap junctions that have an additional influence on con- ability (delayed until the effective refractory period ends). duction properties. In other words, the wavelength must be shorter than the Panel A shows the three cells in the strand at rest with path length. If, for example, the impulse conducted at a a resting potential of inside –90 mV negative with respect normal velocity of 50 cm/sec in a reentrant pathway in to the outside (red line above cells), within the normal the atrium, with an effective refractory period of 150 ms, range for atrial and ventricular cells. In Panel B, cell A is it would have to conduct for at least 150 ms before it could excited and inward INa (red arrows) generates an action return and reexcite a region it had previously excited. potential (above the cell in red), with the inside of the cell This means the conduction pathway must be at least 7.5 becoming +30 mV with respect to the outside (also within cm long (the value of the wavelength, λ = θ (50 cm/sec) × the normal range). The juxtaposition of the excited cell (1) ERP (0.15 sec) for reentry to occur. Such long reentrant and the adjacent unexcited cells (2 and 3) results in flow of pathways, functionally isolated from the rest of the heart, positive charges intracellularly (referred to as the axial are not likely to occur. current) between excited (cell 1) and unexcited cells (2 and According to the concepts described in Figures 9-1 and 3) (from positive to negative) through the gap junction 9-2, the length of the pathway necessary for reentry can be connections, indicated by the curved blue arrows (Panel shortened if the conduction velocity is slowed. For exam- B). The current, when large enough, can flow for several ple, if conduction velocity is slowed to 0.05 cm/sec, as can cells (from cell 1 to cells 2 and 3) as shown in the diagram. occur in diseased cardiac muscle, the reentrant circuit Some of the axial current (capacitive current) supplies need be no more than 7.5 mm in length, which can readily positive charges to the inside of the membranes of the exist. A slow conduction velocity can be a consequence of downstream cells (2 and 3), depolarizing their membrane changes in active membrane properties determining the potential to the threshold potential (~ –70 mV) so that characteristics of inward currents depolarizing the mem- they generate action potentials (red action potentials brane (phase 0) during the action potential or it can be a above cells 2 and 3 in Panel C). consequence of changes in passive properties governing the flow of current between cardiac cells through gap junctional channels; the axial current. Both often partici- pate simultaneously. The factors that affect conduction velocity are described in the next section. 202 ¢ Chapter 9: Basic Principles of Reentry: Altered Conduction and Reentrant Excitation

Figure 9-4 Diagram of conduction in a linear strand of three cells (rectangles 1–3) connected by gap junctional channels (yellow). Necessary Electrophysiological Properties for Reentry ¢ 203

In Panel B, ionic current also flows out of cells 2 and 3 influence how much axial current flows to unexcited sites through the IK1 channel (green rectangles). In extracellu- ahead of the propagating wavefront, the distance at which lar space, current generated by the transmembrane current the current can depolarize the membrane potential to flow in cells 2 and 3, flows from these cells back to the threshold, and the amount of current needed to depolar- excited cell, from positive to negative (blue arrows right to ize the sink to threshold. left), completing the circuit. This is the current detected in An additional factor that must be kept in mind, but electrogram and ECG recordings. The excited cell (1) gen- that is usually not emphasized, is the resistance to current erating the current in Panel B is the “source,” the unexcited flow in the extracellular space, which is part of the local cell(s) (2 and 3) are the “sink.” The action potential has electrical circuit. The extracellular space is actually com- conducted from cell 1 to cells 2 and 3 in Panel C (cell 1 has partmentalized into the microvascular tree and interstitial repolarized to reestablish its resting membrane potential space. Only the resistance (impedance) of the interstitial of –90 mV, red line above cell). Once threshold is reached space affects current flow. The microvascular tree is insu- and an action potential is generated in cells 2 and 3, the lated from the interstitial space. Therefore, changes in newly excited cells switch from being a sink to being a extracellular resistance will also affect conduction veloc- source, generating axial current to depolarize down- ity. However, the influence of changes in extracellular stream cells, perpetuating the process of action potential space with disease on conduction is uncertain. One (impulse) propagation (Panel C). example might be that an increase in interstitial fluid Safety factor. For normal conduction to occur, the could decrease extracellular resistance to enhance velocity number of positive charges delivered by the source to the but this effect might be offset by changes in the other fac- sink (Figure 9-4, Panel B cell 1) should be greater than the tors that affect conduction. number of positive charges leaving the cells at the sink (cells Na+ channel properties. Figure 9-4, Panel D shows 2 and 3). This property is responsible for depolarization of the effects of a reduction in the inward current at the the membrane potential to threshold for generation of the source, in a cell with a reduced resting potential of –65 action potential in cells of the sink. There is an “impedance mV (0 potential not shown for measurement of resting match” between the source and the sink, meaning that the potential) that inactivates a fraction of Na+ channels,

resistance to axial current flow (impedance) allows suffi- decreasing the net inward INa (see Chapter 4, Figure 4-5 cient axial current that “matches” the requirements for for a description of the effects of resting membrane depo- depolarization of the sink to threshold potential. The ability larization on the Na+ channel). In cell 1, the decreased

to conduct from one cell to the next can be expressed in rate (dv/dtmax) and amount of current during phase 0 terms of the “safety factor” for conduction. This is a mea- depolarizes the membrane potential only to +5 mV (red surement of reliability (robustness) of conduction expressed action potential), reducing the amount of source and as the ratio of the amount of net current generated by the axial current (blue arrows). This in turn decreases the source (cell 1) to the minimal amount of current required to rapidity at which cells in the pathway of propagation are excite the neighboring sink cells (2 and 3). A safety factor depolarized to threshold potential and the distance in greater than 1 indicates more than sufficient current gener- front of the propagating action potential that is depolar- ated by the source for propagation, while a safety factor less ized (axial current flows only to cell 2 in the diagram), than 1 causes propagation to fail because the sink is not slowing conduction. A further reduction in axial current depolarized to threshold potential. In myocardial cells with caused by inactivation of more Na+ channels would lead

phase 0 caused by INa the safety factor is about 1.5 whereas to conduction block when source current is insufficient to it is smaller in the SA and A-V nodes (but still sufficient for depolarize the sink to threshold.

propagation) that have depolarization phases dependent on The relationship of INa to conduction velocity, deter- the relatively weak ICaL. mined in a computer model, is shown in Figure 9-5. INa is expressed on the abscissa as membrane excitability or the + - Determinants of Conduction Velocity percent of maximum Na conductance (%gNa), a mea- The conduction velocity depends on (1) the properties surement of the ease at which ions flow through the of the ionic current generated by the source (magnitude channel. Conduction velocity on the left (ordinate) slows by about two-thirds to 17 cm/sec as %g-Na decreases before and speed to reach maximum intensity (dv/dtmax), (2) the resistance to intracellular and intercellular current flow block occurs (horizontal bar at end of solid curved line), between source and sink, which is the axial resistance or although in studies on tissue, velocity may be slower. The impedance, provided by myoplasm and gap junctions, and safety factor for conduction (dashed line, right ordinate) (3) the membrane properties of the sink. These properties also decreases in parallel until conduction blocks when the safety factor falls below 1.